The hypothesis to be tested in this proposal is that individual differences in responsiveness to stressors are in part attributable to different kinds and/or degrees of brain lateralization. Research conducted in this laboratory, and in others, has established that normal rats have functional and neurochemical asymmetries in several brain regions. Much of this work has focused on the dopamine-containing nigrostriatal pathways: asymmetries in striatal dopaminergic function have been related to rats' circling or rotational behavior. There is also evidence that the frontal cortex and nucleus accumbens modulate nigrostriatal asymmetry and that the dopaminergic mesocortical and mesolimbic pathways can be activated by stressors. Recent work has shown that uncontrollable footshock stress can have differential effects on rats having left- and right-sided rotational preferences. These effects are accompanied by lateralized differences in mesoprefrontalcortical dopamine neurochemistry. The goal of this proposal is to characterize, both behaviorally and neurochemically, asymmetric effects of stress. Part of this inquiry will utilize an animal model of depression. We will investigate the respective roles of the left and right frontal cortex in determining these responses in experiments using lesions and intracerebral drug injections. Using in vivo microdialysis, brain neurochemical mechanisms underlying differential responses to stressors in left- and right-lateralized rats will be studied; stress effects on neurotransmitter (dopamine, norepinephrine, serotonin) release will be assessed bilaterally in the corpus striatum, nucleus accumbens and medial prefrontal cortex. Lastly, the role of brain lateralization in understanding current and potential therapies for ameliorating stress- induced disorders will be investigated: both pharmacological (antidepressant drugs) and behavioral interventions will be examined; for the latter, an attempt will be made to alter left- and right-sided stress effects using an operant conditioning technique to reverse rats' rotational preferences. These studies should identify aspects of brain lateralization that are important in determining the nature of the organisms response to stressors and the bases for susceptibility to depressive states.